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European Heart Journal Advance Access published online on February 25, 2005
European Heart Journal, doi:10.1093/eurheartj/ehi175
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European Heart Journal © The European Society of Cardiology 2005; all rights reserved

Preclinical research

Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition--a magnetic resonance imaging study

Juan F. Viles-Gonzalez 1, Valentin Fuster 2, Roberto Corti 3, Carolina Valdiviezo 4, Randolph Hutter 4, Stefano Corda 5, Sunil X. Anand 1, and Juan J. Badimon 1*

1 Cardiovascular Biology Research Laboratory, Cardiovascular Institute, PO Box 1030, Mount Sinai School of Medicine, New York, NY 10029, USA; The Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA
2 The Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA
3 University Hospital of Zurich, Zurich Switzerland
4 Cardiovascular Biology Research Laboratory, Cardiovascular Institute, PO Box 1030, Mount Sinai School of Medicine, New York, NY 10029, USA
5 IRIS, Courbevoie, France

* To whom correspondence should be addressed.
Juan J. Badimon, E-mail: juan.badimon{at}mssm.edu


  Abstract

Aims Endothelial dysfunction, platelet hyperactivity, and inflammation play a crucial role in atherogenesis. A growing body of evidence suggests that inhibition of the thromboxane A2 (TxA2 or TP) receptor may improve endothelial function and reduce the inflammatory component of atherosclerosis in addition to its demonstrated antiplatelet activity. Consequently, we sought to assess the effect of a novel TP receptor antagonist S18886, on atherosclerotic lesion progression and composition by serial non-invasive magnetic resonance imaging (MRI).

Methods and results S18886 was compared with control in an experimental model of established aortic atherosclerosis in New Zealand White rabbits (n = 10). The animals underwent MRI of the abdominal aorta at the time of randomization and at the end of treatment. Subsequently, animals were euthanized and specimens were stained for histopathology and immunohistochemistry with anti-{alpha}-actin antibodies for vascular smooth muscle cells (VSMC), anti-RAM-11 for macrophages, anti-caspase-3 for apoptotic cells, anti-MMP-1 for metalloproteinases, and anti-endothelin-1 (ET-1) as a marker of endothelial dysfunction. MRI analysis revealed a significant reduction in total vessel area (TVA) and vessel wall area (VWA) in the S18886 group (P < 0.05). Immunostaining analysis showed a significant decrease in RAM-11, caspase-3, MMP-1, ET-1 and an increase in {alpha}-actin in the treated group (P < 0.05 vs. control).

Conclusion Inhibition of the TP receptor by S18886 causes a regression of advanced atherosclerotic plaques. In addition, the reduction in the markers for macrophages, apoptotic cells, metalloproteinases, and endothelin-1 and the increase in VSMC, suggests that S18886 may not only halt the progression of atherosclerosis, but also transform lesions towards a more stable phenotype. The possibility of combining antithrombotic and antiatherosclerotic activity by means of the administration of TP inhibitors deserves further investigation in a clinical setting.

Keywords: Thromboxane A2; Thromboxane receptor; TP receptor; Atherosclerosis; Platelets; Antiplatelets; Magnetic resonance imaging; MRI.
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